ORAL LICHEN PLANUS: A DISEASE OR A SPECTRUM OF TISSUE
37
1 ORAL LICHEN PLANUS: A DISEASE OR A SPECTRUM OF TISSUE REACTIONS? TYPES, CAUSES, DIAGNOSTIC ALGORHYTHMS, PROGNOSIS, MANAGEMENT STRATEGIES Marco Carrozzo, 1 Stephen Porter, 2 Valeria Mercadante, 2 Stefano Fedele 2, 3 1 Prof. Marco Carrozzo, Professor of Oral Medicine. Centre for Oral Health Research, Oral Medicine Department, Newcastle University, Framlington Place, NE2 4BW, Newcastle upon Tyne UK. Telephone: +4401912086797; Fax: +44 191 208 6137 2 Prof Stephen Porter, Director and Professor of Oral Medicine. UCL Eastman Dental Institute, University College London, 256 Gray’s Inn Road, London WC1X 8LD, UK 2 Dr Valeria Mercadante, Clinical Research Associate. UCL Eastman Dental Institute, University College London, 256 Gray’s Inn Road, London WC1X 8LD, UK 3 Dr Stefano Fedele, Clinical Senior Lecturer and Honorary Consultant in Oral Medicine, UCL Eastman Dental Institute, University College London, 256 Gray’s Inn Road, London WC1X 8LD, UK, NIHR University College London Hospitals Biomedical Research Centre, Maple House, Suite A, 1st floor, 149 Tottenham Court Road, London W1T 7DN, UK; Corresponding author: Dr Stefano Fedele ([email protected])
ORAL LICHEN PLANUS: A DISEASE OR A SPECTRUM OF TISSUE
1
ORAL LICHEN PLANUS: A DISEASE OR A SPECTRUM OF TISSUE
REACTIONS?
TYPES, CAUSES, DIAGNOSTIC ALGORHYTHMS, PROGNOSIS, MANAGEMENT
STRATEGIES
Marco Carrozzo,1 Stephen Porter,2 Valeria Mercadante, 2 Stefano
Fedele 2, 3
1 Prof. Marco Carrozzo, Professor of Oral Medicine. Centre for Oral
Health Research, Oral
Medicine Department, Newcastle University, Framlington Place, NE2
4BW, Newcastle upon
Tyne UK. Telephone: +4401912086797; Fax: +44 191 208 6137
2 Prof Stephen Porter, Director and Professor of Oral Medicine. UCL
Eastman Dental
Institute, University College London, 256 Gray’s Inn Road, London
WC1X 8LD, UK
2 Dr Valeria Mercadante, Clinical Research Associate. UCL Eastman
Dental Institute,
University College London, 256 Gray’s Inn Road, London WC1X 8LD,
UK
3 Dr Stefano Fedele, Clinical Senior Lecturer and Honorary
Consultant in Oral Medicine,
UCL Eastman Dental Institute, University College London, 256 Gray’s
Inn Road, London
WC1X 8LD, UK, NIHR University College London Hospitals Biomedical
Research Centre,
Maple House, Suite A, 1st floor, 149 Tottenham Court Road, London
W1T 7DN, UK;
Corresponding author:
2
Abstract
Oral lichen planus and lichenoid lesions (OLP/OLL) comprise a group
of disorders of the oral
mucosa that likely represent a common reaction pattern to one or
more unknown antigens.
The coexistence of hyperkeratotic striation/reticulation, varying
degrees of mucosal
inflammation from mild erythema to severe widespread ulceration and
a band-like infiltrate of
mononuclear inflammatory cells including activated T lymphocytes,
macrophages and
dendritic cells are considered suggestive of OLP/OLL. Several
classification systems of
OLP/OLL have been attempted, though none seem to be comprehensive.
In this paper we
present a classification of OLP/OLL that includes oral lichen
planus, oral lichenoid contact
lesions, oral lichenoid drug reactions, oral lichenoid lesions of
graft versus host disease,
discoid lupus erythematosus, and systemic lupus erythematosus,
lichen planus-like variant of
paraneoplastic pemphigus/paraneoplastic autoimmune multi-organ
syndrome, chronic
ulcerative stomatitis, lichen planus pemphigoides, solitary fixed
drug eruptions and lichen
sclerosus. We present the clinical and diagnostic aspects of
OLP/OLL and discuss related
treatment options.
3
Introduction
Oral lichen planus and lichenoid lesions (OLP/OLL) comprise a group
of disorders of the oral
mucosa that likely represent a common reaction pattern in response
to extrinsic antigens,
altered self-antigens or super antigens (89). Historically, there
have been unresolved debates
and controversies around the OLP/OLL terminology. The latter term
has been frequently used
to refer to oral lesions that have clinical and histopathological
features similar to OLP but no
risk of malignant transformation or to indicate an uncertain
diagnosis of OLP. However,
definitive clinical and histological diagnostic criteria able to
distinguish OLP from OLL are still
lacking (89). Furthermore, there remains no consensus regarding the
possible different clinical
behaviour of the disorders in the OLP/OLL group with respect to
cancer development. In
Dermatology, the concept of “lichenoid tissue reaction/interface
dermatitis” (LTR/IFD) was
introduced a long time ago to define a number of distinct
inflammatory cutaneous diseases
sharing common histopathological features including
liquefactive/vacuolar changes of the
basal keratinocytes and a sub-epithelial band-like array of
mononuclear inflammatory cells
including activated T lymphocytes, macrophages and dendritic cells
(89,156). During the 2006
World Workshop in Oral Medicine IV, it was proposed to classify the
OLP/OLL group in four
distinct disorders including OLP, oral lichenoid drug reactions
(OLDR) caused by systemic
drug exposure, oral lichenoid contact lesions (OLCL) triggered by
local hypersensitive reaction
to dental materials and oral lichenoid lesions of graft-versus-host
disease (GVHD) (2).
Although a step forward, this classification failed to provide
clear and reliable clinical and
histological criteria to properly differentiate these three types
of OLL from OLP. In addition,
several other disease entities characterised by clinical and/or
histological features of LTR/IFD
were excluded from the classification. Other authors have proposed
alternative classifications
(42,76,173). Overall, there remains no consensus on classification,
diagnostic criteria, clinical
behaviour and management of the OLP/OLL (1,28,174).
In this review, we have attempted to (i) update the classification
of OLP/OLL, (ii) suggest
pragmatic diagnostic criteria and (iii) define a management
strategy.
4
Classification
Table 1 lists the main disorders displaying histological and/or
clinical characteristics of this
OLL/OLP group. Some of these disorders are apparently uncommon
whereas others are
poorly defined or may simply represent a misnomer.
Oral Lichen Planus
OLP is the prototype disorder of the group. Despite the lack of
reliable epidemiological data,
OLP is thought to be relatively common, affecting approximately
1–2% of the population (147).
OLP lesions are chronic and rarely undergo spontaneous remission
(28); they can cause
significant pain and morbidity and most authors would agree that
they can undergo malignant
transformation (52). OLP most commonly affects middle-aged adults
of both sexes, with a
slight female predominance, and without any apparent racial
predilection (48). The distinctive
clinical features of OLP are represented by the presence of white
papules that enlarge and
coalesce to form a reticular, annular or plaque-like pattern, the
so-called Wickham’s striae
(28). Erythema, erosion and ulceration can also occur, often in
association with white striae
(Figure 1). The most commonly affected sites are the buccal mucosa
bilaterally, the borders
and dorsum of the tongue and the gingiva, whereas the palate
(either hard or soft), the lips
and the floor of the mouth are less commonly affected.
Reticular/papular lesions are rarely
symptomatic and patients are often unaware of their presence,
whereas erythematous and
erosive/ulcerative lesions usually result in a varying degree of
discomfort or pain. When
erosive/ulcerative lesions are predominant, confusion with diseases
such as pemphigus
vulgaris, mucous membrane pemphigoid (MMP) and persistent erythema
multiforme (EM) is
common (28,48,147). Long lasting OLP lesions can be predominantly
plaque-like, particularly
in smokers; in the absence of typical reticular/papular lesions,
this can raise significant
diagnostic difficulties with other diseases such as oral
leukoplakia. It should also be mentioned
that dyskeratosis congenita can sometimes present with lichenoid
features (64), and therefore
all putative paediatric OLP cases should be carefully investigated
for nail dystrophies,
abnormal reticulate skin pigmentation, and haematological
abnormalities. Individuals with OLP
5
can also have extra-oral manifestations of lichen planus. The most
frequent extra-oral site in
females is the genital mucosa, with lesions developing in
approximately 20% of women with
OLP (61). The association of concomitant lichenoid lesions/lichen
planus on the vulva, vagina
and gingiva has been termed “vulvo-vaginal-gingival syndrome”.
Conversely, cutaneous
lesions develop in just approximately 15% of patients with OLP
(48). OLP is suggested to
represent a T-cell-mediated immunological response to an unknown
antigenic change in the
skin or oral mucosa in predisposed patients (89). A key, early
event in OLP pathogenesis is
the genetically enhanced increased production of TH1 cytokines,
particularly interferon-
gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α). However, a
recent study has
suggested that Th2-mediated inflammation can also contribute to OLP
pathogenesis and
progression through and can be induced by myeloid dendritic cells
(mDCs), which in turn are
activated by Thymic stromal lymphopoietin (TSLP) secreted by
epithelial cells (185). Cytokine
polymorphisms seem also to influence whether lesions would develop
just in the mouth (IFN-
γ associated) or also on the skin (TNF-α associated) (26). A recent
meta-analysis has
confirmed the association between -308 G/A polymorphism in TNF-α
gene and OLP (84).
Studies of T cell receptor-variable region genes have also
highlighted that OLP is likely to be
the common outcome of a limited combination of extrinsic antigens,
altered self-antigens or
super antigens (167). Three meta-analyses have confirmed that OLP
is associated with
hepatitis C virus (HCV) (98,100,132), which could be also involved
in disease pathogenesis
(133). Although the malignant potential of OLP remains
controversial, a number of small
uncontrolled studies and three large retrospective controlled
studies from Denmark, Sweden
and Italy, using strict diagnostic criteria, have strongly
suggested that OLP patients do carry a
significantly higher risk of developing oral squamous cell
carcinoma (OSCC) than the general
population (57,71,140). A recent systematic review has suggested an
overall rate of
transformation of up to 3.5% (52). The clinical manifestations
alone, particularly when
presenting in the ‘classic’ bilateral keratotic reticular or
papular form, may sometimes allow
diagnosis (28) (Figure 1). However, given the chronic course and
pleomorphic clinical
manifestations, the need for long-term treatment and monitoring,
and the risk of malignant
6
transformation, a confirmatory surgical biopsy appears to represent
prudent clinical practice.
Histopathological confirmation is also important before starting an
active treatment, as a
common cause of therapy failure is inappropriate diagnosis (28).
Histopathological
assessment of OLP can however be difficult (173), although the
assessment of the presence
of dysplasia or malignancy is usually straightforward. Direct
immunofluorescence (DIF) testing
may be of diagnostic help in patients presenting with predominantly
erosive/ulcerative OLP,
so as to exclude other autoimmune blistering/ulcerative diseases.
DIF of OLP is usually
negative or can show shaggy fibrinogen deposits at the epithelial
basement membrane zone
or the so-called cytoid bodies (Russell bodies) (67). Sometimes,
further immunological testing
such as salt-split-skin, indirect immunofluorescence,
immunoblot/immunoprecipitation and
ELISAs are needed in order to achieve a definitive diagnosis and
differentiate OLP from other
blistering disorders, especially MMP (17). However, these
techniques are costly, time-
demanding and not widely available (25).
Oral Lichenoid Contact Lesions (OLCL)
Oral lichenoid contact lesion (OLCL) is a term used to describe
oral lesions that resemble OLP
both clinically and histopathologically but are thought to be
caused by a localised (contact)
hypersensitivity reaction to dental restorative materials, mainly
amalgam (8,112). Dental
amalgam alloy is composed of a mixture of approximately equal parts
of liquid mercury and a
powder consisting of silver (∼22–32%), tin (∼14%), copper (∼8%),
and other trace metals,
including zinc (81). OLCLs to amalgams are supposed to represent a
delayed hypersensitivity
reaction (Coombs and Gell classification: type IV) to low-level
mercury exposure (112).
However, an animal model has failed to definitively prove that
amalgam fillings can cause
OLCL (46). A more recent study using the same animal model
(Brown-Norway Rats) but with
different exposure modalities, suggests that non-toxic mercury can
rather cause lupus-like oral
mucosal lesions (149).
Patch tests are commonly used to identify patients with suspected
hypersensitivity reactions
but their usefulness in OLCL have shown conflicting results (167).
Skin testing is preferable to
7
mucosal testing due to a higher sensitivity and specificity and
because allergen concentration
on mucosa needs to be 5–12 times higher than skin, potentially
exposing patients to the risk
of a toxic reaction. In vitro lymphocyte proliferation has been
employed as an adjunctive tool
in the diagnosis of allergies to various drugs (124) and metals
(12), with the aim of re-
stimulating antigen-specific lymphocytes (memory cells) from
peripheral blood. The assay has
a variety of modifications and names, for example, LTT (lymphocyte
transformation test), LST
(lymphocyte stimulation test), LPT (lymphocyte proliferation test),
or MELISA® (memory
lymphocyte immunostimulation assay). However, this test seems of
limited utility to OLCL (29).
The clinical appearance of OLCL has been rarely described in
details. It is thought that OLCLs
are less symmetrical and more commonly unilateral than OLP but
supporting evidence
remains scarce. Similarly, the close proximity of the lesions with
amalgam restorations is
commonly but not invariably reported (Figure 2). According to the
published pictures, OLCLs
might lack the typical reticular appearance of OLP and be more
commonly patch-like or
atrophic. They are usually located on posterior buccal mucosae and
borders of the tongue.
Histopathology could aid diagnosis if it shows a mixed cell
sub-epithelial infiltrate and a deeper
diffuse distribution in lamina propria. However, OLCL are often
undistinguishable from other
OLLs and OLP on histopathology assessment. There is also
insufficient evidence to support
routine removal of all amalgam restorations in patients with
OLP⁄OLCL (8), although some
authors have reported an improvement in 90% of the lesions after
amalgam replacement in
individuals with positive patch tests and lichenoid lesions in
close contact with amalgam fillings
(167).
Oral Lichenoid Drug Reactions (OLDR)
OLDR are caused by or associated with exposure to certain
medications (2). They are thought
to be uncommon compared to cutaneous lichenoid drug reactions but
reliable data are scarce
and OLDR are likely to be under-reported. The list of drugs that
can cause OLDR is vast and
includes angiotensin-converting enzyme inhibitors (ACE),
non-steroidal anti-inflammatory
inhibitors (NSAIDs), oral hypoglycaemic drugs, penicillamine, gold,
beta-blockers,
8
antifungals (e.g. ketoconazole), anticonvulsants (e.g.
carbamazepine), immunomodulatory
drugs (e.g. gold salts and penicillamine), sulfasalazine, and
lithium (188). Recently, tumour
necrosis factor alpha (TNF-α) inhibitors infliximab and adalimumab
have been reported in
association with OLDR (5). OLDR may occur at any time, even years
after the start of a certain
drug therapy (163), although in many cases there seems to be a
relatively clear temporal
association between the use of the suspected medication and the
onset of the oral lesions (2).
There is currently no specific test for OLDR. Clinical appearance
is unclear particularly
compared to other OLLs, though the unilateral location may aid
diagnosis (91).
Histopathologically OLDR can present a sub-epithelial inflammatory
infiltrate containing
conspicuous eosinophils and/or plasma cells, which is more diffuse
and extends more deeply
than OLP, or has a perivascular appearance (45). Notably, none of
these characteristics has
been consistently reported and other OLL may present similar
histopathological features, such
as discoid lupus erythematosus (DLE) (109). The most reliable
method of diagnosing an
OLDR is to notice resolution after the withdrawal of the putative
drug and the reappearance
when the same drug is reintroduced. However, this is both
impractical and potentially
detrimental for the patient as some reactions may take weeks or
months to resolve and the
medication could be life-saving (2).
Circulating basal cell cytoplasmic antibodies (BCCA) are known to
appear in drug eruptions
and they have been studied in OLDR [38], but outcomes remain
unclear. Autologous and
allogeneic immunofluorescence tests seeking for lichen planus
specific antigen (LPSA) seem
not to aid diagnosis of OLDR (108).
Oral Lichenoid Lesions of Graft Versus Host Disease
(OLL-GVHD)
Graft versus host disease (GVHD) is a major complication in
patients receiving hematopoietic
cell transplant (74). GVHD can be classified in acute or chronic
(cGVHD), depending on the
time to onset from the transplant (threshold is of the order of 100
days); however, the latest
NIH consensus criteria recommend that classification should be
based on characteristic
9
symptoms and signs rather than a rigid temporal definition (51).
Both acute and chronic GVHD
can involve the mouth but lichenoid lesions are more common in the
latter (74). Oro-facial
manifestations occur in up to 80% of patients with cGVHD (74) and
include three separate
disease patterns that can coexist: (i) oral lichenoid lesions
(OLL-GVHD) including reticulation,
ulcerations and mucosal atrophy, (ii) salivary gland dysfunction
with hyposalivation and
persistent dry mouth symptoms and oro-facial fibrosis with
restricted mouth opening (51,182).
The mucosal lesions are very similar to those found in OLP (Figure
3), the salivary gland
infiltrates mimic those found in Sjögren’s syndrome, and the
fibrosis and reduced mouth
opening are similar to the orofacial manifestations of scleroderma,
that is also classified as a
LTR/IFD (74). Histologically OLL-GVHD can be very similar to OLP.
The typical clinical
features of lichenoid lesions together with the history of
allogeneic bone marrow transplant
are often sufficient for the diagnosis of OLL-GVHD. Histological
confirmation of OLL-GVHD is
indicated in the absence of signs and symptoms of other systems or
organs involvement and
in cases of atypical clinical presentation. It is also important to
consider development of
dysplasia or malignancy, especially in patients with long-standing
chronic disease.
Lichen planus-like variant of Paraneoplastic
Pemphigus/Paraneoplastic autoimmune
multi-organ syndrome
Paraneoplastic pemphigus (PNP) is an autoimmune syndrome, first
described in 1990 (3),
characterized by the development of muco-cutaneous lesions in
individuals with a neoplastic,
often malignant, disease. Although affected patients often present
with blisters and ulceration
similar to those of pemphigus vulgaris (hence the term PNP), the
disorder can present a
spectrum of clinical and histopathological manifestations that have
been classified into 5
variants: 1) pemphigus-like, 2) pemphigoid-like, 3) erythema
multiforme-like, 4) graft-vs-host
disease-like, and 5) lichen planus-like. More recently, due to
increasing evidence of the
involvement of internal organs as one of the potential
manifestations of the disease, the term
"paraneoplastic autoimmune multiorgan syndrome” (PAMS) was
introduced (119). Lichen
planus-like variant of PNP/PAMS is frequently associated with
Castleman’s disease, which is
10
a rare non-clonal neoplasm of lymphatic origin, also known as giant
lymph node hyperplasia
or benign giant cell lymphoma (122). Castleman's disease most
commonly develops in
lymphatic areas in the retroperitoneal spaces or in the chest and
there is evidence that lesions
may be present for very long periods of time before PNP/PAMS
develops. The most common
histological variant of Castleman's disease associated with
PNP/PMAS is the hyaline vascular
type (122).
PNP/PAMS is characterized by the presence of autoantibodies against
multiple antigens,
particularly the plakin family of proteins, which are part of the
intracellular plaque of the
desmosomes and/or hemidesmosomes. These include the 210 kDa
envoplakin (EP), the 190
kDa periplakin (PP), the 230 kDa bullous pemphigoid antigen BP230,
the 250 and 210 kDa
desmoplakins I and II (DSPI and DSPII), and the 500 kDa plectin.
Other antigens include the
desmogleins (Dsg) 1 and 3, plakophilin 3, desmocollins 1-3 and the
previously described 170
kDa autoantigen recently identified as the protease inhibitor
alpha-2-macroglobulin-like-1
(A2ML1) (146). There seems to be an association with HLA-Cw*14 and
in DRB1*03 in
Chinese and French patients, respectively (68,97), which is yet to
be confirmed in other
populations. In case of any recent or suspicious history of a
neoplasm in patients developing
oral or mucocutaneous lichenoid lesions a diagnosis of PNP/PAMS
should be considered.
Clinically, these patients have severe mucocutaneous lesions and
can develop respiratory
failure. They are typically refractory to standard treatment. Oral
and skin manifestations are
usually pleomorphic and can show a confusing and overlapping array
of lesions (Figure 4).
Histopathology is normally not of great aid. Routine immunologic
tests such as direct and
indirect immunofluorescence (IIF) can be either negative or
controversial showing features of
more than one disease entity. IIF analysis of PNP/PAMS sera
demonstrates the presence of
anti-epidermal antibodies that recognize both the epithelial cell
surface of keratinocytes,
typically seen in pemphigus vulgaris, and the basement membrane
zone, seen in pemphigoid.
The use of special substrates such as rat bladder epithelium that
does not contain Dsg1 and
3 but does contain DSP, EP and PP greatly increases sensitivity
(75-86%) and specificity (83-
98%) (68,97). Several commercially available ELISAs are able to
detect reactivity against
11
some PNP antigens. In particular, an ELISA based on the N–terminal
domain of EP is able to
detect reactivity of 80.6% PNP patient sera (135). Immunoblotting
can show a distinctive
profile of antibodies directed toward the plakin family that
include EP, PP, DSP, BPAG1, and
plectin. However, the gold standard for diagnosis is still
represented by immunoprecipitation
(IP) of keratinocyte extracts. Historically, the first technique
used to identify PNP
autoantibodies was IP using radioactively labelled keratinocyte
extracts (3). The sensitivity of
this technique is superior to immunoblotting, IIF on rat bladder,
and EP-ELISA. In addition, IP
is able to identify anti-A2ML1 reactivity that is not detected by
IB with PNP sera (146).
However, because of the use of radioactive material, this technique
is not widely available.
Recently, non-radioactive IP has been introduced and it seems to
have similar diagnostic
performance (134).
Lichenoid lesions of Discoid Lupus Erythematosus
The term lupus erythematosus (LE) refers to a group of connective
tissue disorders comprising
at least three major disease subsets: 1) Systemic lupus
erythematosus (SLE); 2) Subacute
cutaneous LE (SCLE) and 3) Discoid lupus erythematosus (DLE). SLE
and DLE can give rise
to oral lichenoid lesions, which may appear similar if not
identical to those of OLP.
Immunofluorescent studies may be occasionally useful to distinguish
oral lesions of LE from
OLP (121) but they cannot always distinguish between the two
disorders (117). The presence
of mixed clinical and histopathological features of LE and LP, has
been referred to as lupus
erythematosus/ lichen planus overlap syndrome (LE/LP overlap
syndrome) (117).
DLE is the common form of chronic cutaneous LE and can be separated
into two groups:
localized and generalized. The widespread disease is more
frequently associated with
abnormalities detected in laboratory tests (125). DLE has been
associated with HLA region
genes and non-MHC loci (see Table1) but the evidence is weaker than
in SLE (79,80,118).
The disease may be confined to the skin, especially on sun-exposed
areas, such as face, ears
and scalp, but there may be also mucosal involvement which is
usually limited to the oral and
anogenital mucosae (18,82,113,141,166,172,179,181). Up to 28% of
patients with DLE are
12
susceptible to developing SLE (35). Oral lichenoid lesions occur in
15–20% of DLE cases but
the prevalence of DLE limited to the oral mucosa is unknown and
rarely studied. The buccal
mucosa, the vermilion, the gingiva and palate are usually affected.
Typical oral lesions are
characterised by central atrophic areas or shallow erosions,
radiating white striae at margins,
characteristically far less sharply defined than in OLP. They are
often unilateral, and may be
on the hard and soft palate, and outer aspect of the lips which OLP
usually spares. They can
be the sole manifestation of the disease. Lip lesions can tend to
spread from the vermilion to
the surrounding lip skin, obscuring the limits of the vermilion but
this is not a constant feature
(120). Squamous cell carcinoma may rarely arise in longstanding
lesions of oral DLE (99).
Patients with DLE rarely fulfil 4 or more of the criteria used to
classify SLE (161). Serologic
abnormalities are particularly uncommon in localized disease. The
predominant autoantibody
in DLE patients remains unknown and only low-titre anti-Ro (60 kDa)
antibodies have been
found in DLE patients (36). Histopathology can sometimes be of help
but frequently is
equivocal or not specific, particularly in distinguishing DLE from
OLP (168). On direct
immunofluorescence testing granular deposition of immunoglobulin
and/or complement can
be seen at the dermo-epidermal junction, the so called lupus band
test (LBT): this is
characteristic but not pathognomonic of either DLE or SLE. The LBT
is neither sensitive nor
specific and has mostly been replaced by advances in serologic
testing (73).
Lichenoid Lesions of Systemic Lupus Erythematosus
SLE is regarded as a prototypic systemic autoimmune disease, which
can affect multiple
organs and systems. Genome-wide association studies and mapping of
candidate regions
have allowed a better understanding of the genetic basis of SLE
(65). A meta-analysis found
the most consistent HLA association with HLA-DR3 and DR2 in
European populations (50),
whereas a genome-wide association study (GWAS) revealed a greater
association with MSH5
gene, which is in the class III region (66). Table 1 lists the
candidate gene associations
confirmed by GWAS. Given the large number of SLE susceptibility
loci known, it seems that
the genetic risk of SLE is derived from variations in several
genes, each being of modest effect
13
size (65). SLE most often manifests as a mixture of constitutional
symptoms, with skin,
musculoskeletal, and hematologic involvement. However, some
patients present with
predominantly hematologic, renal, or neuropsychiatric
manifestations (58). Cutaneous
manifestations of SLE are present in 85% of patients during the
course of the disease. The
most typical skin lesion of LE is erythema over the malar eminences
of the face and bridge of
the nose (the so called butterfly rash). Oral lesions appear in up
to 40 % of cases of SLE and
can rarely be the presenting sign of the disease (85,86). Oral
manifestations of SLE can be
similar to DLE: oral lichenoid lesions with atrophy, erosion and
hyperkeratotic reticulation and
striation (Figure 5). Histopathological and immunofluorescence
features have been discussed
above in the DLE section. Otherwise unspecific oral ulcerations can
also be seen and they
are an American College of Rheumatologists (ACR) criterion for SLE
diagnosis (111).
According to the ACR, the diagnosis of SLE requires the presence of
four or more of 11 criteria,
serially or simultaneously, during any period of observation (58).
Diagnosis of SLE is also
challenging because typical symptoms and signs could take long time
to establish. The
diagnosis should be confirmed by the pattern of autoantibodies,
particularly anti-nuclear
antibodies (ANA). Further to double-stranded DNA autoantibodies
other autoantibodies are
commonly detected in SLE. Some SLE autoantibodies are pathogenic
and others are
protective and some appear to be neutral, indifferent, and/or have
roles that may not be
directly traced to pathogenesis or protection (55).
Chronic Ulcerative Stomatitis
In 1990 Jaremko et al. (78) described a disease, which they named
chronic ulcerative
stomatitis (CUS), characterized by chronic oral ulcerations that
occasionally can involve the
skin (23,38,43,53,75,152,153,155,183). The clinical appearance of
oral lesions of CUS is
reminiscent of OLP and specific features able to differentiate CUS
from OLP are virtually non-
existant. Some authors report that CUS should be considered in
patients unresponsive to
glucocorticosteroid therapy (53). No more than 40 cases have been
reported since the original
description and it is still unclear if this disease exists as a
separate entity from OLP. The
14
similar to OLP. Diagnosis of CUS requires immunofluorescence (IF)
microscopic examination
(138). Direct IF reveals the presence of IgG antibodies bound to of
keratinocytes nuclei of the
basal and lower one-third cell layers, with a unique stratified
epithelial specific-antinuclear
antibody (SES-ANA) pattern (78). However, other disorders such as
SLE, scleroderma and
CREST (Calcinosis, Raynaud’s phenomenon, Oesophageal involvement,
Sclerodactyly and
Telangectasia) syndrome, and mixed connective tissue disease
(MCTD), may demonstrate a
similar ANA pattern (152). CUS patients also have circulating
antibodies which exhibit the
SES-ANA pattern on indirect IF (IIF) using an oesophagus substrate
(78). Circulating IgG in
SLE, CREST, and MCTD patients (38,127,175) are usually detected
using human neoplastic
HEp-2 cells or rodent kidney cells as substrates but they are not
suitable for IIF of suspected
CUS cases. SLE, scleroderma and MCTD may also be positive for ANA
on oesophagus
substrates but the pattern is different because the antibodies
should be distributed through
the superficial epithelial layers (152). Immunoblot studies led to
the recognition of a 70-kDa
keratinocyte protein in some CUS cases (16,24,128). Further studies
identified a nuclear
protein normally present in basal and parabasal cells of stratified
squamous epithelia called
deltaNp63alpha (Δnp63α), which is thought to be the putative
specific CUS antigen (93).
Δnp63α is a member of a family of nuclear transcription factors,
including p63, p73, and the
p53 tumor suppressor gene, which share considerable sequence
homology (34). It is still
debated if Δnp63α is specific of CUS as some Authors reported that
OLP patients could have
circulating autoantibodies against this protein (128). Two novel
non-commercial ELISA
systems have been developed to detect antibodies against Δnp63α
(47,154).
Lichen Planus Pemphigoides
Lichen planus pemphigoides (LPP) is a rare clinical variant of
bullous pemphigoid (BP), which
is characterized by clinical and histological features of both LP
and BP. This immuno-bullous
disorder usually occurs on skin and occasionally involves the oral
mucosa (154,180,189). Less
than 80 cases have been reported so far and about 40% reported oral
lesions similar to those
15
of OLP (189). Only 3 cases of LPP limited to the oral mucosa have
been published (114,154),
though similar clinical appearance and immunological testing led to
a MMP diagnosis in at
least another published case (92). LLP seems to have a similar
demographic to OLP, with a
slight female predominance and mean age at diagnosis of 54 years
(189). LPP has been
associated with a wide variety of conditions including malignancies
such as lymphoma,
haemangiopericytoma, and colon cancer, and other conditions and
therapies such as viral
hepatitis, phototherapy (UVA, UVB/psoralen-UVA), and therapy with
simvastatin, furosemide,
ramipril, captopril, cinnarizine, paracetamol and ibuprofen
(63,105,114,123,158). Clinically,
LPP is characterized by formation of blisters or tense bullae prior
to, during, or after a papular
eruption of cutaneous LP. The bullae arise on both normal and LP
affected skin (39,154).
Clinical features of oral involvement in LPP are lichenoid
striation, erythematous and ulcerative
lesions involving gingiva, buccal mucosa but also the palate
(Figure 6). Classic diagnosis of
LPP is made by clinical, histopathologic and immunologic features
that suggest the
concurrence of both LP and BP (39,154,160). Histopathology shows
features of
orthokeratosis, hypergranulosis, irregular acanthosis, hydropic
degeneration of basal
keratinocytes with citoid body formation and subepidermal clefting
(at the level of the lamina
lucida). The dermal inflammatory infiltrate is inconstant and may
be cell-rich or cell-poor,
lichenoid or perivascular; in addition, eosinophilic spongiosis may
also be a feature
(144,154,187). The sub-epidermal blister shows linear deposition of
IgG and/or C3 along the
dermal-epidermal junction (DEJ) upon DIF. In addition, more than
50% of LPP cases have
circulating IgG anti-BMZ antibodies that are deposited on the
epidermal side of 1.0 M sodium
chloride split skin indirect immunofluorescence. By immunoblot,
sera of LPP patients react
against BP180, a component of the hemidesmosome involved in the
dermo-epidermal
anchoring complex. In particular, autoantibodies bind to the
C-terminal portion of NC16A, a
non-collagenous region of BP180 recognized by the vast majority of
BP and MMP patients
(10,190). In this context, the commercially available ELISA based
on NC16A can contribute to
the diagnosis.
Mixed Group
Lichenoid lesions on the inner side of the lip, possibly initiated
by microbial plaque
accumulation on the buccal surfaces of the anterior teeth, have
been reported as a possible
new disease entity (9,107). All subjects presented with a localized
erythematous patch on the
labial mucosa of the upper lip and microscopically the lesions were
characterized by the
presence of lichenoid inflammation with concomitant granulomatous
inflammation.
Solitary fixed drug eruptions on the lip have been rarely reported.
They are characterized by
a peculiar sudden onset of solitary, or occasionally multiple, well
demarcated erythematous
lesions on the mucous membranes which may or may not become
ulcerated. The
histopathology shows lichenoid interface dermatitis that includes
plasma cells and tends to
surround small vessels (130). The diagnostic hallmark is the
reappearance of the lesion
precisely over the previously affected site when the offending
agent is reused.
Lichen sclerosus (LC) is clinically characterized by the
development of well-delimited
hyperkeratotic lesions to the skin and genitals, and very rarely to
the oral mucosa, followed by
fibrosis/sclerosis (7,83). It can mimic other disorders causing
hyperkeratotic patches including
OLP. Histopathology of LC shows epithelial atrophy, local hydropic
degeneration of the basal
cells, loss of the epithelial crests, and homogenization of the
underlying connective tissue with
a reduction in elastic fibre presence, hyalinization and connective
tissue sclerosis. Lichenoid
lymphocytic infiltrate is often present but does not show a
distinct band of lymphocytes at the
epithelial–connective tissue junction as in OLP and other lichenoid
lesions (7).
Differential Diagnosis of OLL
Occasionally the diagnosis of a specific OLL may be made on visual
inspection without any
further test but in most instances other investigations are
warranted (Figure 7). OLL often
present overlapping clinical and histopathological features and
diagnosis is frequently
challenging. A complete history and clinical assessment by a
multidisciplinary group of
specialists may be required to investigate oral, skin, nail, scalp,
genital, oesophageal,
laryngeal and conjunctival involvement.
The clinical features alone, particularly when presenting in the
“classic” hyperkeratotic reticular
bilateral form, would often support the exclusion of other oral
keratotic disease such as
leukoplakia, frictional keratosis and proliferative verrucous
leucoplakia (156). The latter is
particularly difficult to address as available reports suggest that
it can show histological
“lichenoid” features. Biopsy would be prudent clinical practice in
most, if not all, patients.
Histopathology, however, can be subjective and nonspecific (28);
also it is unlikely to allow
differentiation between OLL. Further investigations such as direct
and salt-split skin indirect
immunofluorescence and ELISA tests may be needed when a bullous
disorders or LPP and
CUS are suspected. In cases of recalcitrant and atypical
muco-cutaneous manifestations,
further investigations are warranted including a PET-scan for total
body cancer screening if
PNP/PAMS is suspected. Immunoblotting, IP and ELISAs may also
assist diagnosis (Figure
7).
When medical history, clinical features and immunological findings
(for example positive ANA
test) suggest SLE, testing fro anti-DNA antibodies as well as and
other autoantibodies
including Anti-Sm, anti-RNP, anti-Ro/SSA and La/SSB,
anti-antiphospholipid and anti-
cardiolipin should be considered (Table 1) (Figure 7) (55). For
some OLL such as DLE, OLDR
and OLCL, reliable diagnostic tests are not available and further
research is warranted.
Management of OLP/OLL
Some OLL such as OLP, OLCL, OLDR, DLE and CUS are more amenable to
topical therapy
than PNP/PAMS, SLE and LPP, which usually require systemic
medications and
multidisciplinary management. This chapter will focus upon topical
therapy of OLP/OLL.
In individuals with potential OLDR, the causing medication should
be discontinued where
possible. This is often difficult because the drug is usually
important to the patient’s health and
effective alternative drugs may not be available. Moreover, the
lesions may persist for several
months following withdrawal of the medication (109). Patients
suspected to have OLCL may
benefit from targeted amalgam replacement, although it is possible
that simple polishing of
the restorations and improvement of the patient’s oral hygiene may
minimize plaque
18
accumulation and frictional trauma to the mucosa and therefore
results in an improvement of
the OLCL. Patients obviously should be counselled on benefits and
risks of amalgam removal.
Also, the cyclic nature of the disease characterized by periods of
spontaneous remission and
exacerbation, the limited evidence supporting amalgam replacement,
and the unpredictability
of the amalgam removal procedure should be described. Risks should
be fully disclosed: these
include potential iatrogenic dental damage, the possibility of the
worsening of the lesions
immediately after amalgam replacement (especially if a rubber dam
is not used), shorter life
span of some alternative materials, and possible additional
allergic reactions involving any of
the newly placed restoration materials (8).
The main aim of any therapy of OLP/OLL is symptomatic control
(28,164). Usually, patients
with reticular and other asymptomatic lesions do not require active
treatment. The elimination
of potential precipitating or provoking factors is an important
initial step in the management of
symptomatic OLP/OLL. Precipitating factors and irritants (sharp or
fractured teeth, poorly
fitting dentures, alcohol and tobacco consumption) should be
identified and avoided or
eliminated where possible (73). Good oral hygiene along with the
use of chlorhexidine mouth
rinse should also be advocated, as plaque reduction may have
beneficial effects on the lesions
(70).
As many cases of OLP/OLL are chronic, the patient's medical
history, psychological state, and
treatment compliance as well as possible drug interaction must be
considered when evaluating
the cost effectiveness of any treatment modality (27).
Although a permanent cure is not available, various treatment
regimens (Table 2) have been
introduced to reduce and control painful symptoms of OLP/OLL.
Curiously, several suggested
treatment modalities are also suspected to induce lichenoid lesions
(Table 2). Topical agents
are usually the first line of therapy as they have few adverse side
effects. However, systemic
agents may be required if lesions are widespread and involve the
skin or other mucosae, or if
there is recalcitrant disease. The medications that are commonly
used for OLP/OLL are
immunosuppressive and few were developed specifically for oral
disease. As a result, there is
a lack of adequate studies determining their efficacy (164).
Moreover, several aspects of the
19
therapy such as optimal dose, duration of treatment, safety, and
true efficacy remain largely
unknown (148). Patients should be warned about the off-label use of
the medications used to
treat OLP/OLL.
Topical corticosteroids
dosage regimen represents “standard of care” (164).
Commonly, ointments and suspensions are preferred whereas creams
can have a bitter taste
and do not melt well with adhesive pastes whereas gels almost
invariably contain alcohol and
sting. Sprays, normally used for nasal allergy and asthma, can be
also used intra-orally.
A reduction in painful symptoms with mid-potency corticosteroids,
such as triamcinolone
acetonide 0.1% and betamethasone, potent fluorinated
corticosteroids such as fluocinolone
acetonide 0.1% and fluocinonide 0.05%, and super potent halogenated
corticosteroids, such
as clobetasol propionate 0.05%, have been reported in 30–100% of
treated patients
(15,20,21,103,139,165,177). The adherence to the oral mucosa for a
sufficient length of time
can be enhanced using adhesive pastes, such as sodium carboxymethyl
cellulose (Orabase®)
and hydroxyethyl cellulose, or special drug delivery systems, such
as lipid-loaded
microspheres (19,21,103,116). Iatrogenic Cushing's syndrome has
been rarely reported using
TCS (44,59,94) whereas acute pseudo-membranous candidiasis is the
most common adverse
side effect. This can be prevented with the use of antifungals
(miconazole gel) or chlorhexidine
mouthwashes (21,101). When lesions of OLP/OLL are limited to the
gingivae topical steroids
may be best delivered using custom made trays (60).
Other topical agents
be beneficial for symptomatic OLP/OLL, especially if the lesions
are recalcitrant to
20
corticosteroids. Cyclosporine has been used as a mouthrinse
(50-1500 mg/day) (127) or in
adhesive bases (26-48 mg/day) (40,49,77,96,151,178) but is
expensive, not always effective,
and less beneficial than topical clobetasol in inducing clinical
improvement (40). Tacrolimus is
10–100 times as potent as cyclosporine and has greater percutaneous
absorption. Several
uncontrolled, not randomised studies have documented the efficacy
and safety of this agent
in the management of recalcitrant erosive OLL at concentrations
ranging from 0.03% up to
0.1% (41,69,87,95,115,126,142). Burning on application is a common
side-effect and is
observed in <20% of patients. Circulating therapeutic levels of
tacrolimus can be
demonstrated after topical application and occasionally they can
cause systemic adverse
events (41). Pimecrolimus is the newest calcineurin inhibitor used
in OLP/OLL treatment. Its
immunosuppressive potency is thought to be weaker than cyclosporine
and tacrolimus and it
has lower permeation through the skin than topical steroids or
topical tacrolimus.
Nevertheless, a recent RCT comparing pimecrolimus 1% versus
tacrolimus 0.1% in adhesive
ointment in the management of symptomatic OLP/OLL did not show any
difference in clinical
efficacy (4). Although four small placebo-controlled randomised
trials suggested that 1%
pimecrolimus cream can be an effective and well-tolerated treatment
for erosive OLP/OLL
(110,129,159,176), a very recent meta-analysis (129,159,176)
reported that in fact there is no
robust evidence that pimecrolimus is more effective than placebo
(164).
The US Food and Drugs Administration issued a “Black Box” warning
regarding the use of
tacrolimus and pimecrolimus because of a possible increased risk of
malignancy development
(squamous cell carcinoma and lymphoma) in patients using topical
tacrolimus/pimecrolimus
for cutaneous diseases. The decision has been heavily criticized in
the medical community as
the concern stemmed from case reports and animal data (150). A
recent ‘deductive meta-
analysis’ found no evidence of increased risk of skin cancer
associated with the use of TCIs
(162). The issue remains controversial, as two separate papers
reported development of oral
SCC in two patients with OLP/OLL and history of topical tacrolimus
0.1% therapy (11,106).
Topical rapamycin (Sirolimus), which inhibits the response to
interleukin-2 (IL-2) and blocks
activation of T- and B-cells, has been recently suggested to
represent an effective alternative
21
therapy in refractory erosive OLP (157). Notably, rapamycin has
both immunosuppressive and
tumour inhibitor properties, and might theoretically control
painful symptoms and at the same
time lessen the risk of cancer development in OLP/OLL
patients.
Topical retinoids such as tretinoin, isotretinoin, fenretinide and
tezarotene are generally less
effective than topical corticosteroids and more likely to cause
adverse side effects
(13,14,131,145,170).
Systemic corticosteroids are recommended for patients with severe
painful OLP/OLL who
have failed to respond to topical therapy or have widespread
OLP/OLL involving skin, genitals,
oesophagus, or scalp (22). Prednisolone at a starting dosage of 40
to 80 mg daily for 1-4
weeks is usually sufficient to achieve a notable response, often
followed by slow reduction in
dosage. However recurrences are common and therefore systemic
corticosteroids do not
represent a sensible therapeutic option in chronic OLP/OLL (102)
due to their toxicity profile
associated with long-term therapy. Corticosteroid-sparing agents
and other
immunosuppressants including azathioprine and mycophenolate mofetil
are usually required
for long-term therapy (32,33,54,136,169,186), though there has been
little robust evaluation
of their efficacy in the OLP/OLL population. Hydroxychloroquine
sulphate is considered the
first-line systemic therapy for severe DLE (82) but it could be
also effective for CUS.
Also, very recently, biologic agents including Basiliximab,
Etanercept, Efalizumab and
Alefacept have been proposed for treatment of OLP/OLL (Table 2),
especially for patients with
severe manifestations or those who have failed traditional first-
and second-line therapy such
as topical corticosteroids/topical calcineurin inhibitors.
Non-pharmacological modalities such
as phototherapy (62), surgery (6) and laser treatment (with carbon
dioxide and low-dose
excimer 308-nm laser) (72,90,171) have been suggested but their
effectiveness is yet to be
proven. Of note, surgical intervention has been reported to worsen
lesions of OLP/OLL (88).
Novel treatments
22
Topical aloe vera (AV) (37,104,137,143) and oral curcuminoids (OC)
(30,31) have been
suggested to represent promising therapeutic options for OLP/OLL.
However, different AV
formulations have been published so far and the amount of active
product can vary greatly
depending on the age of the plant, the growing and harvesting
conditions, the parts of the
plant, and the extraction methods used. Further, OC can cause
adverse side effects in up to
40% of the patients, including liver dysfunction.
Amlexanox (56) and topical thalidomide (184) have also been
investigated and were reported
to be effective in controlling painful symptoms of OLP/OLL in
comparison to weak topical
corticosteroids, which are no longer commonly used for OLP/OLL
management.
Conclusions
OLP/OLL represent a heterogeneous group of inflammatory disorders
that are characterised
by similar clinical manifestations and histopathological features.
They probably share a
common reaction pattern to one or more antigens, however the exact
pathogenic mechanisms
and the nature of antigenic triggers remain unknown. Oral
manifestations typically include
“lichenoid” hyperkeratotic striation/reticulation and/or a variable
degree of erythema, blistering,
erosion and ulceration, which are seen in oral lichen planus, oral
lichenoid contact lesions,
oral lichenoid drug reactions, oral lichenoid lesions of graft
versus host disease, discoid lupus
erythematosus, and systemic lupus erythematosus, lichen planus-like
variant of
paraneoplastic pemphigus/paraneoplastic autoimmune multi-organ
syndrome, chronic
ulcerative stomatitis, lichen planus pemphigoides, solitary fixed
drug eruptions and oral lichen
sclerosus. Histologically OLP/OLL are characterised by a
“lichenoid” sub-epithelial
inflammatory infiltrate of lymphocytes. With the exception of oral
lichen planus and sclerosus,
oral lichenoid contact lesions, oral lichenoid drug reactions, and
chronic ulcerative stomatitis,
affected patients often present a variety of extra-oral systemic
manifestations that require
assessment and management. Oral painful lesions of OLP/OLL are
commonly managed with
topical corticosteroids and immunosuppressants, although severe
recalcitrant disease and
extra-oral manifestations typically require systemic
immunosuppression. Some of the
23
disorders in the OLP/OLL group are associated with an increased
risk of oral cancer
development and should be carefully and regularly monitored.
24
References
1. Aguirre Urizar JM. Letter to the editor: Oral lichenoid disease.
A new classification proposal. Med Oral Patol Oral Cirugia Bucal
2008: 13: 224.
2. Al-Hashimi I, Schifter M, Lockhart PB, Wray D, Brennan M,
Migliorati CA, Axéll T, Bruce AJ, Carpenter W, Eisenberg E, Epstein
JB, Holmstrup P, Jontell M, Lozada-Nur F, Nair R, Silverman B,
Thongprasom K, Thornhill M, Warnakulasuriya S, van der Waal I. Oral
lichen planus and oral lichenoid lesions: diagnostic and
therapeutic considerations. Oral Surg Oral Med Oral Pathol Oral
Radiol Endodontology 2007: 103: S25.e1–S25.e12.
3. Anhalt GJ, Kim S, Stanley JR, Korman NJ, Jabs DA, Kory M, Izumi
H, Ratrie III H, Mutasim D, Ariss-Abdo L, Labib RS. The new england
journal of medicine dec. 20, 1990 paraneoplastic pemphigus: An
autoimmune mucocutaneous disease associated with neoplasia. N Engl
J Med 1990: 323: 1729–1735.
4. Arduino PG, Carbone M, Della Ferrera F, Elia A, Conrotto D,
Gambino A, Comba A, Calogiuri PL, Broccoletti R. Pimecrolimus vs.
tacrolimus for the topical treatment of unresponsive oral erosive
lichen planus: A 8 week randomized double-blind controlled study. J
Eur Acad Dermatol Venereol 2014: 28: 475–482.
5. Asarch A, Gottlieb AB, Lee J, Masterpol KS, Scheinman PL,
Stadecker MJ, Massarotti EM, Bush ML. Lichen planus-like eruptions:
An emerging side effect of tumor necrosis factor-α antagonists. J
Am Acad Dermatol 2009: 61: 104–111.
6. Axéll T, Henriksen BM. Treatment of gingival lichen with free
palatal grafts. J Oral Pathol Med 2007: 36: 105–109.
7. Azevedo RS, Romañach MJ, de Almeida OP, Mosqueda-Taylor A,
Vega-Memije ME, Carlos- Bregni R, Contreras-Vidaurre E,
López-Jornet P, Saura-Inglés A, Jorge J. Lichen sclerosus of the
oral mucosa: clinicopathological features of six cases. Int J Oral
Maxillofac Surg 2009: 38: 855– 860.
8. Baccaglini L, Thongprasom K, Carrozzo M, Bigby M. Urban legends
series: Lichen planus. Oral Dis 2013: 19: 128–143.
9. Bäckman K, Jontell M. Microbial-associated oral lichenoid
reactions. Oral Dis 2007: 13: 402– 406.
10. Barnadas MA, Roé E, Dalmau J, Alomar A, Martínez L, Gelpí C.
Lichen planus pemphigoides: Detection of anti-BP 180 antibodies by
ELISA and immunoblotting tests. J Eur Acad Dermatol Venereol 2010:
24: 1360–1361.
11. Becker JC, Houben R, Vetter CS, Bröcker EB. The carcinogenic
potential of tacrolimus ointment beyond immune suppression: A
hypothesis creating case report. BMC Cancer 2006: 6.
doi:10.1186/1471-2407-6-7
12. von Blomberg-van der Flier M, van der Burg CKH, Pos O, van de
Plassche-Boers EM, Bruynzeel DP, Garotta G, Scheper RJ. In vitro
studies in nickel allergy: Diagnostic value of a dual parameter
analysis. J Invest Dermatol 1987: 88: 362–368.
25
13. Boisnic S, Branchet MC, Pascal F, Ben Slama L, Rostin M,
Szpirglas H. Topical tretinoin for treatment of oral lichen planus
and oral leukoplakia: Clinical study. Ann Dermatol Venereol 1994:
121: 459–463.
14. Buajeeb W, Kraivaphan P, Pobrurksa C. Efficacy of topical
retinoic acid compared with topical fluocinolone acetonide in the
treatment of oral lichen planus. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 1997: 83: 21–25.
15. Buajeeb W, Pobrurksa C, Kraivaphan P. Efficacy of fluocinolone
acetonide gel in the treatment of oral lichen planus. Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 2000: 89: 42–45.
16. Cacciapuoti M, Di Marco E, Cozzani E, Zerega B, Cancedda FD,
Parodi A. The antibody to the 70- kd antigen in chronic ulcerative
stomatitis and lichen planus [9]. J Am Acad Dermatol 2004: 50:
486.
17. Calabresi V, Carrozzo M, Cozzani E, Arduino P, Bertolusso G,
Tirone F, Parodi A, Zambruno G, Di Zenzo G. Oral pemphigoid
autoantibodies preferentially target BP180 ectodomain. Clin Immunol
2007: 122: 207–213.
18. Callen JP. Cutaneous lupus erythematosus: A personal approach
to management. Australas J Dermatol 2006: 47: 13–27.
19. Campisi G, Giandalia G, De Caro V, Di Liberto C, Aricò P,
Giannola LI. A new delivery system of clobetasol-17-propionate
(lipid-loaded microspheres 0.025%) compared with a conventional
formulation (lipophilic ointment in a hydrophilic phase 0.025%) in
topical treatment of atrophic/erosive oral lichen planus. A Phase
IV, randomized, observer-blinded, parallel group clinical trial. Br
J Dermatol 2004: 150: 984–990.
20. Carbone M, Arduino PG, Carrozzo M, Caiazzo G, Broccoletti R,
Conrotto D, Bezzo C, Gandolfo S. Topical clobetasol in the
treatment of atrophic-erosive oral lichen planus: A randomized
controlled trial to compare two preparations with different
concentrations. J Oral Pathol Med 2009: 38: 227–233.
21. Carbone M, Conrotto D, Carrozzo M, Broccoletti R, Gandolfo S,
Scully C. Topical corticosteroids in association with miconazole
and chlorhexidine in the long-term management of atrophic- erosive
oral lichen planus: A placebo-controlled and comparative study
between clobetasol and fluocinonide. Oral Dis 1999: 5: 44–49.
22. Carbone M, Goss E, Carrozzo M, Castellano S, Conrotto D,
Broccoletti R, Gandolfo S. Systemic and topical corticosteroid
treatment of oral lichen planus: A comparative study with long-term
follow-up. J Oral Pathol Med 2003: 32: 323–329.
23. Carlson MW, Garlick JA, Solomon LW. Chronic ulcerative
stomatitis: Evidence of autoimmune pathogenesis. Oral Surg Oral Med
Oral Pathol Oral Radiol Endodontology 2011: 111: 742–748.
24. Carrizosa AM, Elorza FL, Camacho FM. Antinuclear antibodies in
patients with lichen planus. Exp Dermatol 1997: 6: 54–56.
25. Carrozzo M. A reappraisal of diagnostic criteria for mucous
membrane pemphigoid. J Oral Pathol Med 2009: 38: 160.
26
26. Carrozzo M, De Capei MU, Dametto E, Fasano ME, Arduino P,
Broccoletti R, Vezza D, Rendine S, Curtoni ES, Gandolfo S. Tumor
Necrosis Factor-α and Interferon-γ Polymorphisms Contribute to
Susceptibility to Oral Lichen Planus. J Invest Dermatol 2004: 122:
87–94.
27. Carrozzo M, Gandolfo S. The management of oral lichen planus.
Oral Dis 1999: 5: 196–205.
28. Carrozzo M, Thorpe R. Oral lichen planus: a review. Minerva
Stomatol 2009: 58: 519–537.
29. Cederbrant K, Gunnarsson L-G, Hultman P, Norda R,
Tibbling-Grahn L. In vitro lymphoprolif erative assays with HgCl2
cannot identify patients with systemic symptoms attributed to
dental amalgam. J Dent Res 1999: 78: 1450–1458.
30. Chainani-Wu N, Madden E, Lozada-Nur F, Silverman Jr. S.
High-dose curcuminoids are efficacious in the reduction in symptoms
and signs of oral lichen planus. J Am Acad Dermatol 2012: 66:
752–760.
31. Chainani-Wu N, Silverman Jr. S, Reingold A, Bostrom A, Mc
Culloch C, Lozada-Nur F, Weintraub J. A randomized,
placebo-controlled, double-blind clinical trial of curcuminoids in
oral lichen planus. Phytomedicine 2007: 14: 437–446.
32. Chang ALS, Badger J, Rehmus W, Kimball AB. Alefacept for
erosive lichen planus: A case series. J Drugs Dermatol 2008: 7:
379–383.
33. Cheng A, Mann C. Oral erosive lichen planus treated with
efalizumab. Arch Dermatol 2006: 142: 680–682.
34. Choi H-R, Batsakis JG, Zhan F, Sturgis E, Luna MA, El-Naggar
AK. Differential expression of p53 gene family members p63 and p73
in head and neck squamous tumorigenesis. Hum Pathol 2002: 33:
158–164.
35. Chong BF, Song J, Olsen NJ. Determining risk factors for
developing systemic lupus erythematosus in patients with discoid
lupus erythematosus. Br J Dermatol 2012: 166: 29–35.
36. Chong BF, Tseng L-C, Lee T, Vasquez R, Li QZ, Zhang S, Karp DR,
Olsen NJ, Mohan C. IgG and IgM autoantibody differences in discoid
and systemic lupus patients. J Invest Dermatol 2012: 132:
2770–2779.
37. Choonhakarn C, Busaracome P, Sripanidkulchai B, Sarakarn P. The
efficacy of aloe vera gel in the treatment of oral lichen planus: A
randomized controlled trial. Br J Dermatol 2008: 158:
573–577.
38. Chorzelski TP, Olszewska M, Jarzabek-Chorzelska M, Jablonska S.
Is chronic ulcerative stomatitis an entity? Clinical and
immunological findings in 18 cases. Eur J Dermatol 1998: 8:
261–265.
39. Cohen DM, Ben-Amitai D, Feinmesser M, Zvulunov A. Childhood
lichen planus pemphigoides: A case report and review of the
literature. Pediatr Dermatol 2009: 26: 569–574.
40. Conrotto D, Carbone M, Carrozzo M, Arduino P, Broccoletti R,
Pentenero M, Gandolfo S. Ciclosporin vs. clobetasol in the topical
management of atrophic and erosive oral lichen planus: A
double-blind, randomized controlled trial. Br J Dermatol 2006: 154:
139–145.
27
41. Conrotto D, Carrozzo M, Ubertalli AV, Gandolfo S, Giaccone L,
Boccadoro M, Benedetto B. Dramatic increase of tacrolimus plasma
concentration during topical treatment for oral graft- versus-host
disease [3]. Transplantation 2006: 82: 1113–1115.
42. Cortés-Ramírez D-A, Gainza-Cirauqui M-L, Echebarria-Goikouria
M-A, Aguirre-Urizar JM. Oral lichenoid disease as a premalignant
condition: The controversies and the unknown. Med Oral Patol Oral
Cirugia Bucal 2009: 14: E118–E122.
43. Cozzani E, Cacciapuoti M, Di Marco E, Zerega B, Cancedda FD,
Parodi A. Patients with oral erosive and cutaneous lichen planus
may have antibodies directed against the chronic ulcerative
stomatitis protein antigen of 70-kDa. Acta Dermatovenerol Alp
Pannonica Adriat 2008: 17: 120–124.
44. Decani S, Federighi V, Baruzzi E, Sardella A, Lodi G.
Iatrogenic Cushing’s syndrome and topical steroid therapy: Case
series and review of the literature. J Dermatol Treat 2014: 25:
495–500.
45. Den Haute VV, Antoine JL, Lachapelle JM. Histopathological
discriminant criteria between lichenoid drug eruption and
idiopathic lichen planus: Retrospective study on selected samples.
Dermatology 1989: 179: 10–13.
46. Dunsche A, Frank MP, Lüttges J, Açil Y, Brasch J, Christophers
E, Springer ING. Lichenoid reactions of murine mucosa associated
with amalgam. Br J Dermatol 2003: 148: 741–748.
47. Ebrahimi M, Nylander E, Bäcklund B, Wahlin Y-B, Coates PJ,
Nylander K. The use of a novel ELISA method for detection of
antibodies against p63 in sera from patients diagnosed with oral
and/or genital and skin lichen planus. J Oral Pathol Med 2010: 39:
486–490.
48. Eisen D, Carrozzo M, Sebastian J-VB, Thongprasom K. Number V.
Oral lichen planus: Clinical features and management. Oral Dis
2005: 11: 338–349.
49. Eisen D, Ellis CN, Duell EA, Griffiths CEM, Voorhees JJ. Effect
of topical cyclosporine rinse on oral lichen planus: A double-blind
analysis. N Engl J Med 1990: 323: 290–294.
50. Fernando MM, Stevens CR, Sabeti PC, Walsh EC, McWhinnie AJ,
Shah A, Green T, Rioux JD, Vyse TJ. Identification of two
independent risk factors for lupus within the MHC in United Kingdom
families. PLoS Genet 2007: 3.
doi:10.1371/journal.pgen.0030192
51. Filipovich AH. Diagnosis and manifestations of chronic
graft-versus-host disease. Best Pract Res Clin Haematol 2008: 21:
251–257.
52. Fitzpatrick SG, Hirsch SA, Gordon SC. The malignant
transformation of oral lichen planus and oral lichenoid lesions A
systematic review. J Am Dent Assoc 2014: 145: 45–56.
53. Fourie J, van Heerden WF, McEachen SC, van Zyl A. Chronic
ulcerative stomatitis: a distinct clinical entity? SADJ J South Afr
Dent Assoc Tydskr Van Suid-Afr Tandheelkd Ver 2011: 66: 119–
121.
54. Frieling U, Bonsmann G, Schwarz T, Luger TA, Beissert S.
Treatment of severe lichen planus with mycophenolate mofetil. J Am
Acad Dermatol 2003: 49: 1063–1066.
55. Fritzler MJ. Toward a new autoantibody diagnostic orthodoxy:
Understanding the bad, good and indifferent. Autoimmun Highlights
2012: 3: 51–58.
28
56. Fu J, Zhu X, Dan H, Zhou Y, Liu C, Wang F, Li Y, Liu N, Chen Q,
Xu Y, Zeng X, Jiang L. Amlexanox is as effective as dexamethasone
in topical treatment of erosive oral lichen planus: A short-term
pilot study. Oral Surg Oral Med Oral Pathol Oral Radiol 2012: 113:
638–643.
57. Gandolfo S, Richiardi L, Carrozzo M, Broccoletti R, Carbone M,
Pagano M, Vestita C, Rosso S, Merletti F. Risk of oral squamous
cell carcinoma in 402 patients with oral lichen planus: A follow-up
study in an Italian population. Oral Oncol 2004: 40: 77–83.
58. Gladman DD, Urowitz MB, Esdaile JM, Hahn BH, Klippel J, Lahita
R, Liang MH, Schur P, Petri M, Wallace D. Guidelines for referral
and management of systemic lupus erythematosus in adults. Arthritis
Rheum 1999: 42: 1785–1796.
59. Gonzalez-Moles MA, Morales P, Rodriguez-Archilla A, Isabel
IR-A, Gonzalez-Moles S. Treatment of severe chronic oral erosive
lesions with clobetasol propionate in aqueous solution. Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 2002: 93: 264–270.
60. Gonzalez-Moles MA, Ruiz-Avila I, Rodriguez-Archilla A,
Morales-Garcia P, Mesa-Aguado F, Bascones-Martinez A, Bravo M.
Treatment of severe erosive gingival lesions by topical application
of clobetasol propionate in custom trays. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 2003: 95: 688–692.
61. Gümrü B. A retrospective study of 370 patients with oral lichen
planus in Turkey. Med Oral Patol Oral Cirugia Bucal 2013: 18:
e427–e432.
62. Guyot AD, Farhi D, Ingen-Housz-Oro S, Bussel A, Parquet N,
Rabian C, Bachelez H, Francès C. Treatment of refractory erosive
oral lichen planus with extracorporeal photochemotherapy: 12 Cases.
Br J Dermatol 2007: 156: 553–556.
63. Hamada T, Fujimoto W, Okazaki F, Asagoe K, Arata J, Iwatsuki K.
Lichen planus pemphigoides and multiple keratoacanthomas associated
with colon adenocarcinoma [15]. Br J Dermatol 2004: 151:
252–254.
64. Handley TPB, Ogden GR. Dyskeratosis congenita: Oral
hyperkeratosis in association with lichenoid reaction. J Oral
Pathol Med 2006: 35: 508–512.
65. Harley ITW, Kaufman KM, Langefeld CD, Harley JB, Kelly JA.
Genetic susceptibility to SLE: New insights from fine mapping and
genome-wide association studies. Nat Rev Genet 2009: 10:
285–290.
66. Harley JB, Alarcón-Riquelme ME, Criswell LA, Jacob CO, Kimberly
RP, Moser KL, Tsao BP, Vyse TJ, Langefeld CD, Nath SK, Guthridge
JM, Cobb BL, Mirel DB, Marion MC, Williams AH, Divers J, Wang W,
Frank SG, Namjou B, Gabriel SB, Lee AT, Gregersen PK, Behrens TW,
Taylor KE, Fernando M, Zidovetzki R, Gaffney PM, Edberg JC, Rioux
JD, Ojwang JO, James JA, Merrill JT, Gilkeson GS, Seldin MF, Yin H,
Baechler EC, Li Q-Z, Wakeland EK, Bruner GR, Kaufman KM, Kelly JA.
Genome-wide association scan in women with systemic lupus
erythematosus identifies susceptibility variants in ITGAM, PXK,
KIAA1542 and other loci. Nat Genet 2008: 40: 204–210.
67. Helander SD, Rogers III RS. The sensitivity and specificity of
direct immunofluorescence testing in disorders of mucous membranes.
J Am Acad Dermatol 1994: 30: 65–75.
68. Helou J, Allbritton J, Anhalt GJ. Accuracy of indirect
immunofluorescence testing in the diagnosis of paraneoplastic
pemphigus. J Am Acad Dermatol 1995: 32: 441–447.
29
69. Hodgson TA, Sahni N, Kaliakatsou F, Buchanan JAG, Porter SR.
Long-term efficacy and safety of topical tacrolimus in the
management of ulcerative/erosive oral lichen planus. Eur J Dermatol
2003: 13: 466–470.
70. Holmstrup P, Schiøtz AW, Westergaard J. Effect of dental plaque
control on gingival lichen planus. Oral Surg Oral Med Oral Pathol
1990: 69: 585–590.
71. Holmstrup P, Thorn JJ, Rindum J, Pindborg JJ. Malignant
development of lichen planus-affected oral mucosa. J Oral Pathol
1988: 17: 219–225.
72. Huerta Leteurtre N, Bagan Sebastian JV, Cardona Tortajada F,
Lloria de Miguel E, Jimenez Soriano Y, Basterra Alegria J. Oral
lichen planus plaques and homogeneous leukoplasia: Comparative
results of treatment with CO2 laser. Acta Otorrinolaringol Esp
1999: 50: 543–547.
73. Hung T, Crawford RI, Martinka M. Degree of histologic
inflammation in lupus erythematosus and direct immunofluorescence
results: Red and inflamed lesions do not increase the chances of
getting a bright band. J Cutan Med Surg 2013: 17: 22–26.
74. Imanguli MM, Alevizos I, Brown R, Pavletic SZ, Atkinson JC.
Oral graft-versus-host disease. Oral Dis 2008: 14: 396–412.
75. Islam MN, Cohen DM, Ojha J, Stewart CM, Katz J, Bhattacharyya
I. Chronic ulcerative stomatitis: Diagnostic and management
challenges-four new cases and review of literature. Oral Surg Oral
Med Oral Pathol Oral Radiol Endodontology 2007: 104: 194–203.
76. Ismail SB, Kumar SK, Zain RB. Oral lichen planus and lichenoid
reactions: etiopathogenesis, diagnosis, management and malignant
transformation. J Oral Sci 2007: 49: 89–106.
77. Itin P, Surber C, Büchner S. Lack of effect after local
treatment with a new ciclosporin formulation in recalcitrant
erosive oral lichen planus. Dermatology 1992: 185: 262–265.
78. Jaremko WM, Beutner EH, Kumar V, Kipping H, Condry P, Zeid MY,
Kauffman CL, Tatakis DN, Chorzelski TP. Chronic ulcerative
stomatitis associated with a specific immunologic marker. J Am Acad
Dermatol 1990: 22: 215–220.
79. Järvinen TM, Hellquist A, Koskenmies S, Einarsdottir E,
Koskinen LLE, Jeskanen L, Berglind L, Panelius J, Hasan T, Ranki A,
Kere J, Saarialho-Kere U. Tyrosine kinase 2 and interferon
regulatory factor 5 polymorphisms are associated with discoid and
subacute cutaneous lupus erythematosus. Exp Dermatol 2010: 19:
123–131.
80. Järvinen TM, Hellquist A, Koskenmies S, Einarsdottir E,
Panelius J, Hasan T, Julkunen H, Padyukov L, Kvarnström M,
Wahren-Herlenius M, Nyberg F, D’Amato M, Kere J, Saarialho-Kere U.
Polymorphisms of the ITGAM gene confer higher risk of discoid
cutaneous than of systemic lupus erythematosus. PLoS ONE 2010: 5.
doi:10.1371/journal.pone.0014212
81. Jensen SJ. Maximum contents of mercury in dental silver
amalgams. Scand J Dent Res 1985: 93: 84–88.
82. Jessop S, Whitelaw DA, Delamere FM. Drugs for discoid lupus
erythematosus. Cochrane Database Syst Rev Published Online First:
2009. doi:10.1002/14651858.CD002954.pub2
83. Jiménez Y, Gavaldá C, Carbonell E, Margaix M, Sarrión G. Lichen
sclerosus of the oral mucosa: A case report. Med Oral Patol Oral
Cirugia Bucal 2008: 13: E403–E406.
30
84. Jin X, Wang J, Zhu L, Wang L, Dan H, Zeng X, Chen Q.
Association between -308 G/A polymorphism in TNF-α gene and lichen
planus: A meta-analysis. J Dermatol Sci 2012: 68: 127– 134.
85. Jonsson R, Heyden G, Westberg NG, Nyberg G. Oral mucosal
lesions in systemic lupus erythematosus - A clinical,
histopathological and immunopathological study. J Rheumatol 1984:
11: 38–42.
86. Jorizzo JL, Salisbury PL, Rogers III RS, Goldsmith SM, Shar GG,
Callen JP, Wise CM, Semble EL, White WL. Oral lesions in systemic
lupus erythematosus: Do ulcerative lesions represent a necrotizing
vasculitis? J Am Acad Dermatol 1992: 27: 389–394.
87. Kaliakatsou F, Hodgson TA, Lewsey JD, Hegarty AM, Murphy AG,
Porter SR. Management of recalcitrant ulcerative oral lichen planus
with topical tacrolimus. J Am Acad Dermatol 2002: 46: 35–41.
88. Katz J, Goultschin J, Benoliel R, Rotstein I, Pisanty S. Lichen
planus evoked by periodontal surgery. J Clin Periodontol 1988: 15:
263–265.
89. Khudhur AS, Di Zenzo G, Carrozzo M. Oral lichenoid tissue
reactions: Diagnosis and classification. Expert Rev Mol Diagn 2014:
14: 169–184.
90. Köllner K, Wimmershoff M, Landthaler M, Hohenleutner U.
Treatment of oral lichen planus with the 308-nm UVB excimer laser -
Early preliminary results in eight patients. Lasers Surg Med 2003:
33: 158–160.
91. Lamey PJ, McCartan BE, MacDonald DG, MacKie RM. Basal cell
cytoplasmic autoantibodies in oral lichenoid reactions. Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 1995: 79: 44–49.
92. Lee HY, Blazek C, Beltraminelli H, Borradori L. Oral mucous
membrane pemphigoid: Complete response to topical tacrolimus. Acta
Derm Venereol 2011: 91: 604–605.
93. Lee LA, Walsh P, Prater CA, Su L-J, Marchbank A, Egbert TB,
Dellavalle RP, Targoff IN, Kaufman KM, Chorzelski TP, Jablonska S.
Characterization of an autoantigen associated with chronic
ulcerative stomatitis: The CUSP autoantigen is a member of the p53
family. J Invest Dermatol 1999: 113: 146–151.
94. Lehner T, Lyne C. Adrenal function during topical oral
corticosteroid treatment. Br Med J 1969: 4: 138–141.
95. Lener EV, Brieva J, Schachter M, West LE, West DP, El-Azhary
RA. Successful treatment of erosive lichen planus with topical
tacrolimus. Arch Dermatol 2001: 137: 419–422.
96. Levell N, Iain Macleod R, Marks J. Lack of effect of
cyclosporin mouthwash in oral lichen planus. The Lancet 1991: 337:
796–797.
97. Liu AY, Valenzuela R, Helm TN, Camisa C, Melton AL, Bergfeld
WF. Indirect immunofluorescence on rat bladder transitional
epithelium: A test with high specificity for paraneoplastic
pemphigus. J Am Acad Dermatol 1993: 28: 696–699.
98. Liu S, Yao S, Wei W, Tian W, Zhang H, Wang B. Hepatitis C virus
and lichen planus: A reciprocal association determined by a
meta-analysis. Arch Dermatol 2009: 145: 1040–1047.
31
99. Liu W, Shen Z-Y, Wang L-J, Hu Y-H, Shen X-M, Zhou Z-T, Li J.
Malignant potential of oral and labial chronic discoid lupus
erythematosus: A clinicopathological study of 87 cases.
Histopathology 2011: 59: 292–298.
100. Lodi G, Pellicano R, Carrozzo M. Hepatitis C virus infection
and lichen planus: A systematic review with meta-analysis. Oral Dis
2010: 16: 601–612.
101. Lodi G, Tarozzi M, Sardella A, Demarosi F, Canegallo L, Di
Benedetto D, Carrassi A. Miconazole as adjuvant therapy for oral
lichen planus: A double-blind randomized controlled trial. Br J
Dermatol 2007: 156: 1336–1341.
102. Lozada F, Silverman Jr. S, Migliorati C. Adverse side effects
associated with prednisone in the treatment of patients with oral
inflammatory ulcerative diseases. J Am Dent Assoc 1984: 109:
269–270.
103. Lozada-Nur F, Miranda C, Maliksi R. Double-blind clinical
trial of 0.05% clobetasol proprionate ointment in orabase and 0.05%
fluocinonide ointment in orabase in the treatment of patients with
oral vesiculoerosive diseases. Oral Surg Oral Med Oral Pathol 1994:
77: 598–604.
104. Mansourian A, Momen-Heravi F, Saheb-Jamee M, Esfehani M,
Khalilzadeh O, Momen-Beitollahi J. Comparison of aloe vera
mouthwash with triamcinolone acetonide 0.1% on oral lichen planus:
A randomized double-blinded clinical trial. Am J Med Sci 2011: 342:
447–451.
105. Maoz KB, Brenner S. Lichen planus pemphigoides triggered by
narrowband UVB, paracetamol, and ibuprofen, with autoantibodies to
130kDa antigen. Skinmed 2008: 7: 33–36.
106. Mattsson U, Magnusson B, Jontell M. Squamous cell carcinoma in
a patient with oral lichen planus treated with topical application
of tacrolimus. Oral Surg Oral Med Oral Pathol Oral Radiol
Endodontology 2010: 110: e19–e25.
107. Max Robinson C, Oxley JD, Weir J, Eveson JW. Lichenoid and
granulomatous stomatitis: An entity or a non-specific inflammatory
process? J Oral Pathol Med 2006: 35: 262–267.
108. McCartan BE, Lamey P. Lichen planus--specific antigen in oral
lichen planus and oral lichenoid drug eruptions. Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 2000: 89: 585–587.
109. McCartan BE, McCreary CE. Oral lichenoid drug eruptions. Oral
Dis 1997: 3: 58–63.
110. McCaughey C, MacHan M, Bennett R, Zone JJ, Hull CM.
Pimecrolimus 1% cream for oral erosive lichen planus: A 6-week
randomized, double-blind, vehicle-controlled study with a 6-week
open-label extension to assess efficacy and safety. J Eur Acad
Dermatol Venereol 2011: 25: 1061–1067.
111. McCauliffe DP. Cutaneous lupus erythematosus. Semin Cutan Med
Surg 2001: 20: 14–26.
112. McParland H, Warnakulasuriya S. Oral Lichenoid contact lesions
to mercury and dental Amalgam- A review. J Biomed Biotechnol 2012:
2012. doi:10.1155/2012/589569
113. Merola JF, Prystowsky SD, Iversen C, Gomez-Puerta JA, Norton
T, Tsao P, Massarotti E, Schur P, Bermas B, Costenbader KH.
Association of discoid lupus erythematosus with other clinical
manifestations among patients with systemic lupus erythematosus. J
Am Acad Dermatol 2013: 69: 19–24.
32
114. Mignogna MD, Fortuna G, Leuci S, Stasio L, Mezza E, Ruoppo E.
Lichen planus pemphigoides, a possible example of epitope
spreading. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontology
2010: 109: 837–843.
115. Morrison L, Kratochvil III FJ, Gorman A. An open trial of
topical tacrolimus for erosive oral lichen planus. J Am Acad
Dermatol 2002: 47: 617–620.
116. Muzio LL, Della Valle A, Mignogna MD, Pannone G, Bucci P,
Bucci E, Sciubba J. The treatment of oral aphthous ulceration or
erosive lichen planus with topical clobetasol propionate in three
preparations: A clinical and pilot study on 54 patients. J Oral
Pathol Med 2001: 30: 611–617.
117. Nagao K, Chen K-R. A case of lupus erythematosus/lichen planus
overlap syndrome. J Dermatol 2006: 33: 187–190.
118. Namjou B, Kothari PH, Kelly JA, Glenn SB, Ojwang JO, Adler A,
Alarcón-Riquelme ME, Gallant CJ, Boackle SA, Criswell LA, Kimberly
RP, Brown E, Edberg J, Stevens AM, Jacob CO, Tsao BP, Gilkeson GS,
Kamen DL, Merrill JT, Petri M, Goldman RR, Vila LM, Anaya J-M,
Niewold TB, Martin J, Pons-Estel BA, Sabio JM, Callejas JL, Vyse
TJ, Bae S-C, Perrino FW, Freedman BI, Scofield RH, Moser KL,
Gaffney PM, James JA, Langefeld CD, Kaufman KM, Harley JB, Atkinson
JP. Evaluation of the TREX1 gene in a large multi-ancestral lupus
cohort. Genes Immun 2011: 12: 270–279.
119. Nguyen VT, Ndoye A, Bassler KD, Shultz LD, Shields MC, Ruben
BS, Webber RJ, Pittelkow MR, Lynch PJ, Grando SA. Classification,
clinical manifestations, and immunopathological mechanisms of the
epithelial variant of paraneoplastic autoimmune multiorgan
syndrome: A reappraisal of paraneoplastic pemphigus. Arch Dermatol
2001: 137: 193–206.
120. Nico MMS, Vilela MAC, Rivitti EA, Lourenço SV. Oral lesions in
lupus erythematosus: Correlation with cutaneous lesions. Eur J
Dermatol 2008: 18: 376–381.
121. Nieboer C. The reliability of immunofluorescence and
histopathology in the diagnosis of discoid lupus erythematosus and
lichen planus. Br J Dermatol 1987: 116: 189–198.
122. Nikolskaia OV, Nousari CH, Anhalt GJ. Paraneoplastic pemphigus
in association with Castleman’s disease. Br J Dermatol 2003: 149:
1143–1151.
123. Noël B. Lupus erythematosus and other autoimmune diseases
related to statin therapy: A systematic review. J Eur Acad Dermatol
Venereol 2007: 21: 17–24.
124. Nyfeler B, Pichler WJ. The lymphocyte transformation test for
the diagnosis of drug allergy: Sensitivity and specificity. Clin
Exp Allergy 1997: 27: 175–181.
125. Oke V, Wahren-Herlenius M. Cutaneous lupus erythematosus:
Clinical aspects and molecular pathogenesis. J Intern Med 2013:
273: 544–554.
126. Olivier V, Lacour J-P, Mousnier A, Garraffo R, Monteil RA,
Ortonne J-P. Treatment of chronic erosive oral lichen planus with
low concentrations of topical tacrolimus: An open prospective
study. Arch Dermatol 2002: 138: 1335–1338.
127. Parodi A, Cozzani E, Chorzelski TP, Beutner EH, Rebora A. A
molecule of about 70 kd is the immunologic marker of chronic
ulcerative stomatitis. J Am Acad Dermatol 1998: 38: 1005–
1006.
33
128. Parodi A, Cozzani E, Massone C, Rebora A, Priano L, Ghigliotti
G, Balbi P, Rongioletti F, Micalizzi C, Cestari R, Varaldo G,
Barabino G, Cannata G, Drago F, Moreno V, Schiazza L, Muzio G,
Scaparro E, Alibrandi B, Bandelloni R, Ciaccio M, Desirello G,
Isola PM, Ottoboni S, Rampini P, Santoro G, Sorbara S, Virno G.
Prevalence of stratified epithelium-specific antinuclear antibodies
in 138 patients with lichen planus. J Am Acad Dermatol 2007: 56:
974–978.
129. Passeron T, Lacour J-P, Fontas E, Ortonne J-P. Treatment of
oral erosive lichen planus with 1% pimecrolimus cream: A
double-blind, randomized, prospective trial with measurement of
pimecrolimus levels in the blood. Arch Dermatol 2007: 143:
472–476.
130. Pemberton MN, Yar R, Sloan P. Fixed drug eruption to
oxybutynin. Oral Surg Oral Med Oral Pathol Oral Radiol
Endodontology 2008: 106: e19–e21.
131. Petruzzi M, De Benedittis M, Grassi R, Cassano N, Vena G,
Serpico R. Oral lichen planus: A preliminary clinical study on
treatment with tazarotene. Oral Dis 2002: 8: 291–295.
132. Petti S, Rabiei M, De Luca M, Scully C. The magnitude of the
association between hepatitis C virus infection and oral lichen
planus: meta-analysis and case control study.
2011.http://www.scopus.com/inward/record.url?eid=2-s2.0-
79955122439&partnerID=40&md5=fb2e66580e950d11a99926a60aa72ba0
133. Pilli M, Penna A, Zerbini A, Vescovi P, Manfredi M, Negro F,
Carrozzo M, Mori C, Giuberti T, Ferrari C, Missale G. Oral lichen
planus pathogenesis: A role for the HCV-specific cellular immune
response. Hepatology 2002: 36: 1446–1452.
134. Poot AM, Diercks GFH, Kramer D, Schepens I, Klunder G,
Hashimoto T, Borradori L, Jonkman MF, Pas HH. Laboratory diagnosis
of paraneoplastic pemphigus. Br J Dermatol 2013: 169:
1016–1024.
135. Probst C, Schlumberger W, Stöcker W, Recke A, Schmidt E,
Hashimoto T, Zhu XJ, Zillikens D, Komorowski L. Development of
ELISA for the specific determination of autoantibodies against
envoplakin and periplakin in paraneoplastic pemphigus. Clin Chim
Acta 2009: 410: 13–18.
136. Rebora A, Parodi A, Murialdo G. Basiliximab is effective for
erosive lichen planus [4]. Arch Dermatol 2002: 138:
1100–1101.
137. Reddy RL, Reddy RS, Ramesh T, Singh TR, Swapna LA, Laxmi NV.
Randomized trial of aloe vera gel vs triamcinolone acetonide
ointment in the treatment of oral lichen planus. Quintessence Int
Berl Ger 1985 2012: 43: 793–800.
138. Rinaggio J, Crossland DM, Zeid MY. A determination of the
range of oral conditions submitted for microscopic and direct
immunofluorescence analysis. J Periodontol 2007: 78:
1904–1910.
139. Rödström P-O, Hakeberg M, Jontell M, Nordin P. Erosive oral
lichen planus treated with clobetasol propionate and triamcinolone
acetonide in orabase: A double-blind clinical trial. J Dermatol
Treat 1994: 5: 7–10.
140. Rödström P-O, Jontell M, Mattsson U, Holmberg E. Cancer and
oral lichen planus in a Swedish population. Oral Oncol 2004: 40:
131–138.
141. Rothfield N, Sontheimer RD, Bernstein M. Lupus erythematosus:
systemic and cutaneous manifestations. Clin Dermatol 2006: 24:
348–362.
34
142. Rozycki TW, Rogers III RS, Pittelkow MR, McEvoy MT, El-Azhary
RA, Bruce AJ, Fiore JP, Davis MDP. Topical tacrolimus in the
treatment of symptomatic oral lichen planus: A series of 13
patients. J Am Acad Dermatol 2002: 46: 27–34.
143. Salazar-Sánchez N, López-Jornet P, Camacho-Alonso F,
Sánchez-Siles M. Efficacy of topical Aloe vera in patients with
oral lichen planus: A randomized double-blind study. J Oral Pathol
Med 2010: 39: 735–740.
144. Sapadin AN, Phelps RG, Fellner MJ, Kantor I. Lichen planus
pemphigoides presenting with a strikingly unilateral distribution.
Int J Dermatol 1998: 37: 942–946.
145. Scardina GA, Messina P, Carini F, Maresi E. A randomized trial
assessing the effectiveness of different concentrations of
isotretinoin in the management of lichen planus. Int J Oral
Maxillofac Surg 2006: 35: 67–71.
146. Schepens I, Jaunin F, Begre N, Läderach U, Marcus K, Hashimoto
T, Favre B, Borradori L. The protease inhibitor
alpha-2-macroglobuline-like-1 is the p170 antigen recognized by
paraneoplastic pemphigus autoantibodies in human. PLoS ONE 2010: 5.
doi:10.1371/journal.pone.0012250
147. Scully C, Carrozzo M. Oral mucosal disease: Lichen planus. Br
J Oral Maxillofac Surg 2008: 46: 15–21.
148. Scully C, Eisen D, Carrozzo M. Management of oral lichen
planus. Am J Clin Dermatol 2000: 1: 287–306.
149. Seno K, Ohno J, Ota N, Hirofuji T, Taniguchi K. Lupus-like
oral mucosal lesions in mercury- induced autoimmune response in
Brown Norway rats. BMC Immunol 2013: 14.
doi:10.1186/1471-2172-14-47
150. Siegfried EC, Jaworski JC, Hebert AA. Topical calcineurin
inhibitors and lymphoma risk: Evidence update with implications for
daily practice. Am J Clin Dermatol 2013: 14: 163–178.
151. Sieg P, Von Domarus H, Von Zitzewitz V, Iven H, Farber L.
Topical cyclosporin in oral lichen planus: A controlled,
randomized, prospective trial. Br J Dermatol 1995: 132:
790–794.
152. Solomon LW. Chronic ulcerative stomatitis. Oral Dis 2008: 14:
383–389.
153. Solomon LW, Aguirre A, Neiders M, Costales-Spindler A, Jividen
Jr. GJ, Zwick MG, Kumar V. Chronic ulcerative stomatitis: Clinical,
histopathologic, and immunopathologic findings. Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 2003: 96: 718–726.
154. Solomon LW, Helm TN, Stevens C, Neiders ME, Kumar V. Clinical
and immunopathologic findings in oral lichen planus pemphigoides.
Oral Surg Oral Med Oral Pathol Oral Radiol Endodontology 2007: 103:
808–813.
155. Solomon LW, Stark PC, Winter L, Kumar V, Sinha S. ELISA test
for p63 antibodies in chronic ulcerative stomatitis. Oral Dis 2010:
16: 151–155.
156. Sontheimer RD. Lichenoid tissue reaction/interface dermatitis:
Clinical and histological perspectives. J Invest Dermatol 2009:
129: 1088–1099.
35
157. Soria A, Agbo-Godeau S, Taïeb A, Francès C. Treatment of
refractory oral erosive lichen planus with topical rapamycin: 7
Cases. Dermatology 2008: 218: 22–25.
158. Stoebner P-E, Michot C, Ligeron C, Durand L, Meynadier J,
Meunier L. Simvastatin-induced lichen planus pemphigoides. Ann
Dermatol Venereol 2003: 130: 187–190.
159. Swift JC, Rees TD, Plemons JM, Hallmon WW, Wright JC. The
effectiveness of 1% pimecrolimus cream in the treatment of oral
erosive lichen planus. J Periodontol 2005: 76: 627–635.
160. Tamada Y, Yokochi K, Nitta Y, Ikeya T, Hara K, Owaribe K.
Lichen planus pemphigoides: Identification of 180 kd hemidesmosome
antigen. J Am Acad Dermatol 1995: 32: 883–887.
161. Tan E., Cohen AS, Fries J., Masi AT, Mcshane DJ, Rothfield N.,
Schaller J., Talal N, Winchester RJ. The 1982 revised criteria for
the classification of systemic lupus erythrematosus. Arthritis
Rheum 1982: 25: 1271–1277.
162. Tennis P, Gelfand JM, Rothman KJ. Evaluation of cancer risk
related to atopic dermatitis and use of topical calcineurin
inhibitors. Br J Dermatol 2011: 165: 465–473.
163. Thompson DF, Skaehill PA. Drug-induced lichen planus.
Pharmacotherapy 1994: 14: 561–571.
164. Thongprasom K, Carrozzo M, Furness S, Lodi G. Interventions
for treating oral lichen planus. Cochrane Database Syst Rev Online
Published Online First:
2011.http://www.scopus.com/inward/record.url?eid=2-s2.0-
79960987466&partnerID=40&md5=dae25d59777db12caf5cec34963f1120
165. Thongprasom K, Luengvisut P, Wongwatanakij A, Boonjatturus C.
Clinical evaluation in treatment of oral lichen planus with topical
fluocinolone acetonide: A 2-year follow-up. J Oral Pathol Med 2003:
32: 315–322.
166. Thorne JE, Jabs DA, Nikolskaia O, Anhalt G, Nousari HC.
Discoid lupus erythematosus and cicatrizing conjunctivitis:
Clinicopathologic study of two cases. Ocul Immunol Inflamm 2002:
10: 287–292.
167. Thornhill MH, Pemberton MN, Simmons RK, Theaker ED.
Amalgam-contact hypersensitivity lesions and oral lichen planus.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003: 95:
291–299.
168. Togliatto M, Carrozzo M, Conrotto D, Pagano M, Gandolfo S.
Oral lupus erythematosus. Description and analysis of 11 cases.
Minerva Stomatol 2000: 49: 35–40.
169. Torti DC, Jorizzo JL, McCarty MA. Oral lichen planus: A case
series with emphasis on therapy. Arch Dermatol 2007: 143:
511–515.
170. Tradati N, Chiesa F, Rossi N, Grigolato R, Formelli F, Costa
A, de Palo G. Successful topical treatment of oral lichen planus
and leukoplakias with fenretinide (4-HPR). Cancer Lett 1994: 76:
109–111.
171. Trehan M, Taylor CR. Low-Dose Excimer 308-nm Laser for the
Treatment of Oral Lichen Planus. Arch Dermatol 2004: 140:
415–420.
172. Uva L, Miguel D, Pinheiro C, Freitas JP, Marques Gomes M,
Filipe P. Cutaneous manifestations of systemic lupus erythematosus.
Autoimmune Dis 2012: 1. doi:10.1155/2012/834291
36
173. Van der Meij EH, Van der Waal I. Lack of clinicopathologic
correlation in the diagnosis of oral lichen planus based on the
presently available diagnostic criteria and suggestions for
modifications. J Oral Pathol Med 2003: 32: 507–512.
174. Van Der Waal I. Oral lichen planus and oral lichenoid lesions;
a critical appraisal with emphasis on the diagnostic aspects. Med
Oral Patol Oral Cirugia Bucal 2009: 14: E310–E314.
175. Vassileva S. Drug-induced pemphigoid: Bullous and cicatricial.
Clin Dermatol 1998: 16: 379– 387.
176. Volz T, Caroli U, Lüdtke H, Bräutigam M, Kohler-Späth H,
Röcken M, Biedermann T. Pimecrolimus cream 1% in erosive oral lic